Abstract

Changes in DNA methylation are important in development and disease, but not all regulatory elements act in a methylation-dependent (MD) manner. Here, we developed mSTARR-seq, a high-throughput approach to quantify the effects of DNA methylation on regulatory element function. We assay MD activity in 14% of the euchromatic human genome, identify 2,143 MD regulatory elements, and predict MD activity using sequence and chromatin state information. We identify transcription factors associated with higher activity in unmethylated or methylated states, including an association between pioneer transcription factors and methylated DNA. Finally, we use mSTARR-seq to predict DNA methylation-gene expression correlations in primary cells. Our findings provide a map of MD regulatory activity across the human genome, facilitating interpretation of the many emerging associations between methylation and trait variation.